Diabetic foot ulcer

560:. MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers. Balance in the MMP activity is usually achieved by tissue inhibitor of metalloproteinases (TIMP). Rather than absolute concentrations of either two, it is the ratio of MMP and TIMP that maintains the proteolytic balance and this ratio is found to be disturbed in diabetic ulcer. In spite of these findings, the exact mechanism responsible for increased MMP activity in diabetes is not known yet. One possible line of thought considers 29: 918:(TCC) is a specially designed cast designed to take weight of the foot (off-loading) in patients with DFUs. Reducing pressure on the wound by taking weight of the foot has proven to be very effective in DFU treatment. DFUs are a major factor leading to lower leg amputations among the diabetic population in the US with 85% of amputations in diabetics being preceded by a DFU. Furthermore, the 5 year post-amputation mortality rate among diabetics is estimated at 45% for those with neuropathic DFUs. 719: 295:

assembly. Metabolically altered collagen is known to be highly inflexible and prone to break down, particularly over pressure areas. Fibronectin is the major glycoprotein secreted by fibroblasts during initial synthesis of extracellular matrix proteins. It serves important functions, being a chemo-attractant for macrophages, fibroblasts and endothelial cells.

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Approximately 8.8 percent of hospital admissions of diabetic patients are for foot related problems, and such hospital admissions are about 13 days longer than for diabetics without foot related admissions. Approximately 58% of ulcers recur within 3 years and up to 65% recur within 5 years, sometimes

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Approximately 34% of people with diabetes (Type 1 or Type 2 diabetes) will develop a foot ulcer in their lifetime. 18.6 million people worldwide will develop a foot ulcer each year. 15-20% of moderately to severely infected foot ulcers eventually lead to amputation, and the mortality rate of diabetic

768:

The current guideline in the United Kingdom recommends collecting 8-10 pieces of information for predicting the development of foot ulcers. A simpler method proposed by researchers provides a more detailed risk score based on three pieces of information (insensitivity, foot pulse, previous history of

587:

Complications in the diabetic foot and foot-ankle complex are wider and more destructive than expected and may compromise the structure and function of several systems: vascular, nervous, somatosensory, musculoskeletal. Thus, deeper comprehension of the alteration of gait and foot biomechanics in the

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beta (TGF-β) as an active player. Most MMP genes have TGF-β inhibitory element in their promoter regions and thus TGF–β regulates the expression of both MMP and their inhibitor TIMP. In addition to the importance of cell-cell and cell-matrix interactions, all phases of wound healing are controlled by

55:

is a breakdown of the skin and sometimes deeper tissues of the foot that leads to sore formation. It may occur due to a variety of mechanisms. It is thought to occur due to abnormal pressure or mechanical stress chronically applied to the foot, usually with concomitant predisposing conditions such as

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effects on the peripheral sensory system: impaired nerve conduction has a dramatic effect on the peripheral sensory system since it leads to loss of protective sensation under the sole of the foot. This exposes the diabetic foot to thermal or mechanical trauma, and to the late detection of infection

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effects on muscles: Diabetes mellitus causes severe damage to nerve conduction, thus causing a worsening in the management of the related muscle fibers. As a consequence, both intrinsic and extrinsic muscles of the foot-ankle complex are damaged in structure (reduction of muscle volume) and function

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The length of antibiotic courses depend on the severity of the infection and whether bone infection is involved but can range from 1 week to 6 weeks or more. Current recommendations are that antibiotics are only used when there is evidence of infection and continued until there is evidence that the

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evaluated the effects of nutritional supplements or special diets on healing foot ulcers in people with diabetes. The review authors concluded that it's uncertain whether or not nutritional interventions have an effect on foot ulcer healing and that more research is needed to answer this question.

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compared the effectiveness of non-removable pressure relieving interventions, such as casts, with therapeutic shoes, dressings, removable pressure relieving orthotic devices, and surgical interventions. Non-removable pressure relieving interventions, including non-removable casts with an Achilles

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Effective off loading is a key treatment modality for DFUs, particularly those where there is damage to the nerves in the feet (peripheral neuropathy). Along with infection management and vascular assessment, TCC is vital aspect to effectively managing DFUs. TCC is the most effective and reliable

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TCC helps patients to maintain their quality of life. By encasing the patient's complete foot — including the toes and lower leg — in a specialist cast to redistribute weight and pressure from the foot to the lower leg during everyday movements, patients can remain mobile. The manner in which TCC

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The basement membrane that separates the epidermis from the dermal layer and the endothelial basement membrane mainly contains collagen IV that forms a sheet and binds to other extracellular matrix molecules like laminin and proteoglycans. In addition to collagen IV, the epidermal and endothelial

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to the healing tissue. It is evident from the known collagen assembly that the tensile strength is basically due to fibrillar arrangement of collagen molecules, which self-assemble into microfibrils in a longitudinal as well as lateral manner producing extra strength and stability to the collagen

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There are many types of dressings used to treat diabetic foot ulcers such as absorptive fillers, hydrogel dressings, and hydrocolloids. There is no good evidence that one type of dressing is better than another for diabetic foot ulcers. In selecting dressings for chronic non healing wounds it is

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effects on foot morphology (deformities): due to most of the above alterations, a significant imbalance of peripheral musculature and soft tissue occur in the foot which seriously alters its morphology and determines the onset of foot deformities. Most common deformities of the diabetic foot are

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infection has cleared, instead of evidence of ulcer healing. Choice of antibiotic depends on common local bacterial strains known to infect ulcers. Microbiological swabs are believed to be of limited value in identifying causative strain. Microbiological investigation is of value in cases of

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and the resulting collagen abnormalities lead to greater transversal section – i.e. thickening – of tendons and ligaments and a greater coefficient of elasticity. Particularly affected by this process are Plantar Fascia and Achilles Tendon. Both causes lead to increased stiffness of those

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effects on the skin: skin – and the soft tissues immediately underneath the skin – undergo greater compression and shear loading than usual, thus explaining the onset of tissue damage so deeply correlated to traumatic ulceration processes. Besides this, skin of the diabetic foot loses

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show various morphological differences compared to fibroblasts from age matched controls. Diabetic ulcer fibroblasts are usually large and widely spread in the culture flask compared to the spindle shaped morphology of the fibroblasts in age-matched controls. They often show dilated

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are personalised products that relieve pressure on the foot in order to prevent ulcers. The evidence for special footwear to treat foot ulcers is poor but their effectiveness for prevention is well-established. Design features of footwear that are effective in reducing pressure are

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and replace it, generally increasing in number to react to the harm. The process is activated, though perhaps not exclusively, by cells responding to fragments of damaged ECM, and the repairs are made by reassembling the matrix by cells growing on and through it. Because of this,

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Sucrose-octasulfate impregnated dressing is recommended by the International Working Group on the Diabetic Foot Ulcer (IWGDF) for the treatment of non-infected, neuro-ischaemic diabetic foot ulcers that do not show an improvement with a standard of care regimen

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Doctors also use the Wagner Grades to describe the severity of an ulcer. The purpose of the Wagner Grades is to allow specialists to better monitor and treat diabetic foot ulcers. This grading system classifies Diabetic foot ulcers using numbers, from 0 to 5.

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The recent advances in epigenetic modifications, with special focus on aberrant macrophage polarisation is giving increasing evidences that epigenetic modifications might play a vital role in changing the treatment of diabetic foot ulcer in the near future.

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formation. Decrease in growth factors responsible for tissue repair such as TGF-β is documented in diabetic wounds. Thus, reduced levels of TGFβ in diabetes cases lower down the effect of inhibitory regulatory effect on MMP genes and thus cause MMPs to over

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Autologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care is also recommended by IWGDF However, there is only low quality evidence that such treatment is effective in treating diabetic foot ulcer.

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effects on cartilage: similar to what happens to tendons and ligaments, cartilage changes its composition mainly due to the modification of collagen fibers. This increases its stiffness and decreases the range of motion of all joints in the foot and

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Snyder RJ, Frykberg RG, Rogers LC, Applewhite AJ, Bell D, Bohn G, et al. (November 2014). "The management of diabetic foot ulcers through optimal off-loading: building consensus guidelines and practical recommendations to improve outcomes".

1021:- there is very weak evidence to suggest that people with foot ulcers due to diabetes may have improved healing. There is no evidence to suggest that phototherapy improves the quality of life for people with foot ulcers caused by diabetes. 2884:

Litzelman DK, Slemenda CW, Langefeld CD, Hays LM, Welch MA, Bild DE, et al. (July 1993). "Reduction of lower extremity clinical abnormalities in patients with non-insulin-dependent diabetes mellitus. A randomized, controlled trial".

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Continuous diffusion of oxygen (CDO) - CDO delivers continuous oxygen to an occluded, moist wound site at much lower flow rates of 3–12 mL/h for 24 h 7 days a week for up to several weeks or months, depending on the wound status.

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People with loss of feeling in their feet should inspect their feet on a daily basis, to ensure that there are no wounds starting to develop. Monitoring a person's feet can help in predicting the likelihood of developing ulcers.

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studies have been inconsistent. Research needs to be carried out to optimize the parameters of pressure intensity, treatment intervals and exact timing to start negative pressure therapy in the course of chronic wound healing.

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redistributes pressure protects the wound, letting damaged tissue regenerate and heal. TCC also keeps the ankle from rotating during walking, which helps prevent shearing and twisting forces that can further damage the wound.

458:(EcNOS) is activated by the pulsatile flow of blood through vessels. Nitric oxide produced by EcNOS, maintains the diameter of blood vessels and proper blood flow to tissues. In addition to this, nitric oxide also regulates 511:

study. Therefore, interpretation of these observations would be that in spite of high protein production and protein turnover in diabetic ulcer fibroblasts, vesicles containing secretory proteins could not travel along the

637:

Assessment of diabetic foot ulcer includes identifying risk factors such as diabetic peripheral neuropathy, noting that 50 percent of people are asymptomatic, and ruling out other causes of peripheral neuropathy such as

4994:"Enhanced healing of diabetic wounds by topical administration of adipose tissue-derived stromal cells overexpressing stromal-derived factor-1: biodistribution and engraftment analysis by bioluminescent imaging" 1073:. In the United States; Black people, Native Americans, Hispanics and those living in rural areas or those with a lower socioeconomic status have an increased rate of amputations due to diabetic foot ulcers. 106:

is one such metabolic disorder that impedes the normal steps of the wound healing process. Many studies show a prolonged inflammatory phase in diabetic wounds, which causes a delay in the formation of mature

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Loots MA, Lamme EN, Mekkes JR, Bos JD, Middelkoop E (1999). "Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation".

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should be obtained. In those with a high likelihood of osteomyelitis, a combination of x-ray and being able to probe to bone can reliably diagnose osteomyelitis without the need for more advanced imaging. A

195:

may appear on numb areas of the feet and legs, such as metatarsophalangeal joints and the heel region, as a result of pressure or injury which may go unnoticed and eventually become a portal of entry for

1916:

Obayashi K, Akamatsu H, Okano Y, Matsunaga K, Masaki H (February 2006). "Exogenous nitric oxide enhances the synthesis of type I collagen and heat shock protein 47 by normal human dermal fibroblasts".

1988:"Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation" 4581:"Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial" 2977: 921:

TCC has been used for off-loading DFUs in the US since the mid-1960s and is regarded by many practitioners as the "reference standard" for off-loading the bottom surface (sole) of the foot.

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Armstrong DG, Lavery LA, Abu-Rumman P, Espensen EH, Vazquez JR, Nixon BP, Boulton AJ (April 2002). "Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot".

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foot ulcers is 30% at 5 years with a mortality rate of 70% in those with a foot ulcer who receive an above the foot amputation. Foot ulcers and amputations are associated with a reduced

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Galkowska H, Wojewodzka U, Olszewski WL (2006). "Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers".

2741:

Detrixhe, Audrey; Libon, Florence; Mansuy, Marion; Nikkels-Tassoudji, Nazli; Rorive, Andrée; Arrese, Jorge E.; Quatresooz, Pascale; Reginster, Marie-Annick; Nikkels, Arjen F. (2016).

907:. Biologically active bandages that combine hydrogel and hydrocolloid traits are available, however more research needs to be conducted as to the efficacy of this option over others. 3226:

Healy A, Naemi R, Chockalingam N (2014-09-18). "The effectiveness of footwear and other removable off-loading devices in the treatment of diabetic foot ulcers: a systematic review".

2155:

Vaalamo M, Leivo T, Saarialho-Kere U (July 1999). "Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing".

2082:

Rowe DW, Starman BJ, Fujimoto WY, Williams RH (April 1977). "Abnormalities in proliferation and protein synthesis in skin fibroblast cultures from patients with diabetes mellitus".

832:

With regards to infected foot ulcers, the presence of microorganisms is not in itself enough to determine whether an infection is present. Signs of an infection such as erythema,

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Lavery LA, Vela SA, Lavery DC, Quebedeaux TL (August 1996). "Reducing dynamic foot pressures in high-risk diabetic subjects with foot ulcerations. A comparison of treatments".

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Lyundup, A.V.; Balyasin, M.V.; Maksimova, N.V.; Kovina, M.V.; Krasheninnikov, M.E.; Dyuzheva, T.G.; Yakovenko, S.A.; Appolonova, S.A.; Schiöth, H.B.; Klabukov, I.D. (2022).

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https://savelegs.com/negative-pressure-wound-therapy-in-foot-infections-in-diabetics-effect-on-duration-of-antibiotic-therapy-method-negative-pressure-wound-therapy-has-be/

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Jeffcoate WJ, Lipsky BA, Berendt AR, Cavanagh PR, Bus SA, Peters EJ, et al. (December 2008). "Unresolved issues in the management of ulcers of the foot in diabetes".

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The location of the ulcer, its size, shape, depth and whether the tissue is granulating or sloughy needs to be considered. Further considerations include whether there is

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is a metabolic disorder and hence the defects observed in diabetic wound healing are thought to be the result of altered protein and lipid metabolism and thereby abnormal

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are required for proper cross linking of collagen fibers, via proline, to minimize scarring and maximize the tensile strength of healed tissue. Endothelial cell specific

941:

tendon lengthening component, were found to be more effective at healing foot ulcers related to diabetes that therapeutic shoes and other pressure relieving approaches.

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Heuch L, Streak Gomersall J (July 2016). "Effectiveness of offloading methods in preventing primary diabetic foot ulcers in adults with diabetes: a systematic review".

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may not hasten the resolution of diabetic foot ulcer infection. However, it may reduce the need for surgical interventions such as amputations and hospitalizations.

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It occurs in 34% of people with diabetes during their lifetimes, and it is associated with a high morbidity and mortality with 84% of all diabetes-related lower-leg

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and may improve the healing at 6 weeks. However, there was no benefit at one year and the quality of the reviewed trials was inadequate to draw strong conclusions.

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to remove excess fluid and cellular waste that usually prolong the inflammatory phase of wound healing. Despite a straightforward mechanism of action, results of

816:. An aim to improve glycemic control, if poor, may slow disease progression. When osteomyelitis is suspected to be involved in the foot, but not evidenced on an 102:(ECM) that forms the largest component of the dermal skin layer. But in some cases, certain disorders or physiological insult disturbs the wound healing process. 701:

3. A deep ulcer occurs with inflammation of subcutaneous connective tissue or an abscess. This can include infections in the muscle, tendon, joint, and/or bone.

1005:– there is only limited and poor-quality information available regarding the effectiveness of ozone therapy for treating foot ulcers in people with diabetes. 168:

of small and large blood vessels. Prior history of foot disease, foot deformities that produce abnormally high forces of pressure, callus at pressure areas

4192:

Ludwig K, Homer V, Jensen J (November 2019). "Ease of Application and Removal of Common Total-Contact Cast Systems Used in the Podiatric Medical Community".

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represented by a high longitudinal arch (rigid cavus foot), hammer toes and hallux valgus. A completely different morphologic degeneration is represented by

4620:"LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial" 2190:

Wysocki AB, Staiano-Coico L, Grinnell F (July 1993). "Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9".

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enzymes. These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called

804:

Foot ulcers in diabetes require a multidisciplinary team that may include the primary care doctor, a diabetes nurse specialist, a tissue viability nurse,

3118: 2620:"The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review" 745:

There is no high quality researches that evaluate complex intervention of combining two or more preventive strategies in preventing diabetic foot ulcer.

642:

and spinal injury. Diabetic foot ulcers are often misdiagnosed in patients with undiagnosed skin malignancies, especially high-risk in elderly patients.

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to release the products outside. Fibroblasts from diabetic ulcer exhibit proliferative impairment that probably contributes to a decreased production of

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to look for spots on the foot that have higher temperature which indicate the possibility of an ulcer developing. At the same time there is no strong

3145:"Development and validation of a clinical prediction rule for development of diabetic foot ulceration: an analysis of data from five cohort studies" 899:

dressings may have shown a slight advantage over standard dressings, but the quality of the research is of concern. Dressings and creams containing

5407: 674: 3263:"Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review" 552:

migration, tissue re-organization, inflammation and remodeling of the wounded tissue. Due to persistently high concentrations of pro-inflammatory

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Stem cell therapy may represent a treatment for promoting healing of diabetic foot ulcers. Diabetic foot ulcers develop their own, distinctive

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Bus SA, Valk GD, van Deursen RW, Armstrong DG, Caravaggi C, Hlavácek P, et al. (2008). "Specific guidelines on footwear and offloading".

1749:, Decarlo AA, Whitelock J, "Wound and cutaneous injury healing with a nucleic acid encoding perlecan.", published 28 November 2006 5520: 4957:

Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W (April 2012). "The role of stem cells in the treatment of diabetic foot ulcers".

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Jiang H, Ochoa M, Jain V, Ziaie B (2018-08-28). "A laser-customizable insole for selective topical oxygen delivery to diabetic foot ulcers".

3006: 653:

bone and sinus formation should be investigated. Signs of infection require to be considered such as development of grey or yellow tissue,

742:, as well as avoiding injury. Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions. 600:

control and consequently reduced hydration, making it less elastic and thus more vulnerable to the action of increased mechanical stress;

5092:

Basu Mallik S, Jayashree BS, Shenoy RR (May 2018). "Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds".

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concluded that there was no strong evidence about the effects of psychological therapies on diabetic foot ulcer healing and recurrence.

1465:

Scott G (March–April 2013). "The diabetic foot examination: A positive step in the prevention of diabetic foot ulcers and amputation".

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at a different location that the original ulcer. Diabetic foot disease is the leading cause of non-traumatic lower limb amputations.

1011:- there is some low-quality evidence that growth factors may increase the likelihood that diabetic foot ulcers will heal completely. 4665:

Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L, et al. (Cochrane Wounds Group) (May 2016).

704:

4. The tissue around the area of the ulcer (limited to the toes and forefoot) has begun to decay. This condition is called gangrene.

532:

not only needs to be laid down but also must be able to undergo degradation and remodeling to form a mature tissue with appropriate

330:

especially during the second week of wound repair where they provide a temporary matrix with highly hydrative capacity. Binding of

2317:"Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: possible role in diabetic nephropathy" 98:

is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepwise repair of lost

4751:

Fernando ME, Seneviratne RM, Tan YM, Lazzarini PA, Sangla KS, Cunningham M, et al. (Cochrane Wounds Group) (January 2016).

1229: 1610: 2668: 1648: 1550: 1033: 588:

diabetic foot is of great interest and may play a role in the design and onset of preventive as well as therapeutic actions.

5284: 5229: 3192: 2405:

Bennett NT, Schultz GS (July 1993). "Growth factors and wound healing: Part II. Role in normal and chronic wound healing".

3778:

Bergin SM, Wraight P (January 2006). "Silver based wound dressings and topical agents for treating diabetic foot ulcers".

994:

There is low-certainty evidence that negative pressure wound therapy would improve wound healing in diabetic foot ulcers.

176:, impaired ability to look after personal care (e.g. visual impairment) are further risk factors for diabetic foot ulcer. 5725: 698:

2. A deep ulcer penetrates past the surface, down to the ligaments and muscle. There is no abscess or bone involved yet.

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expression. High levels of glucose can decrease perlecan expression in some cells, probably through transcriptional and

290:

predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional

5746: 5199: 3063:"Efficacy of at home monitoring of foot temperature for risk reduction of diabetes-related foot ulcer: A meta-analysis" 1707:"Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds" 769:

ulcers or amputation). This method is not meant to replace people regularly checking their own feet but complement it.

4619: 3929:

Farid K, Farid M, Andrews CM (June 2008). "Total contact casting as part of an adaptive care approach: a case study".

3580: 1951:

Duda DG, Fukumura D, Jain RK (April 2004). "Role of eNOS in neovascularization: NO for endothelial progenitor cells".

1039:

It is unknown that whether intensive or conventional blood glucose control is better for diabetic foot ulcer healing.

5679: 5329: 351: 73: 4239: 3405:"Footwear and insole design features for offloading the diabetic at risk foot-A systematic review and meta-analyses" 836:, fluctuance, swelling, warmth, or discharge should also be present. The most common organism causing infection is 5555: 4320:

Liu Z, Dumville JC, Hinchliffe RJ, Cullum N, Game F, Stubbs N, et al. (Cochrane Wounds Group) (October 2018).

3890:"It's not what you put on, but what you take off: techniques for debriding and off-loading the diabetic foot wound" 508: 3027: 2268:"Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing" 2227:"Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients" 1336: 1105:

or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.

987: 977: 796:

People with loss of feeling in their feet should not walk around barefoot, but use proper footwear at all times.

354:. Wound healing phases especially, granulation, re-epithelization and remodelling exhibit controlled turnover of 4910:"Psychological interventions for treating foot ulcers, and preventing their recurrence, in people with diabetes" 183:

causes loss of pain or feeling in the toes, feet, legs, and arms due to distal nerve damage and low blood flow.

2659:

Ledoux W (2008). "Chapter 20: The Biomechanics of the Diabetic Foot". In Harris GF, Smith PA, Marks RM (eds.).

1667:

Thomas DW, O'Neill ID, Harding KG, Shepherd JP (April 1995). "Cutaneous wound healing: a current perspective".

382: 232:. Dermal skin is primarily a combination of fibroblasts growing in this matrix. The specific species of ECM of 4418:

Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J (October 2015).

3486:

Dumville JC, Lipsky BA, Hoey C, Cruciani M, Fiscon M, Xia J, et al. (Cochrane Wounds Group) (June 2017).

3061:

Golledge J, Fernando ME, Alahakoon C, Lazzarini PA, Aan de Stegge WB, van Netten JJ, Bus SA (September 2022).

707:

5. Gangrene has spread from the localized area of the ulcer to become extensive. This involves the whole foot.

5445: 3863:"Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008." 57: 4579:

Edmonds M, Lázaro-Martínez JL, Alfayate-García JM, Martini J, Petit JM, Rayman G, et al. (March 2018).

793:. Technology for measuring the pressure within the shoes is recommended during designing diabetic footwear. 5485: 5412: 179:

People with diabetes often develop diabetic neuropathy due to several metabolic and neurovascular factors.

5397: 5322: 5317: 845: 251:

and its extracellular matrix components that helps drive various cellular events in a regulated fashion.

161: 69: 2928:

Hoogeveen RC, Dorresteijn JA, Kriegsman DM, Valk GD, et al. (Cochrane Wounds Group) (August 2015).

1566:

Sweitzer SM, Fann SA, Borg TK, Baynes JW, Yost MJ (2006). "What is the future of diabetic wound care?".

5629: 5458: 5265: 591:

Briefly, the effect of diabetes on the main structures of the foot-ankle complex can be summarised as:

561: 435: 4161:

Lewis J, Lipp A (January 2013). "Pressure-relieving interventions for treating diabetic foot ulcers".

4130:

Lewis J, Lipp A (January 2013). "Pressure-relieving interventions for treating diabetic foot ulcers".

1746: 5532: 5480: 5377: 4554: 3353:

van Netten JJ, Raspovic A, Lavery LA, Monteiro-Soares M, Rasmussen A, Sacco IC, Bus SA (March 2020).

961: 537: 220:(or "ECM") is the external structural framework that cells attach to in multicellular organisms. The 138: 3861:

Margolis DJ, Malay DS, Hoffstad OJ, Leonard CE, MaCurdy T, de Nava KL, et al. (February 2011).

5715: 5453: 5260: 884:

There is limited safety and efficacy data of topical antibiotics in treating diabetic foot ulcers.

597: 4618:

Game F, Jeffcoate W, Tarnow L, Jacobsen JL, Whitham DJ, Harrison EF, et al. (November 2018).

5607: 5572: 4714:

Cruciani M, Lipsky BA, Mengoli C, de Lalla F, et al. (Cochrane Wounds Group) (August 2013).

2483:

Vileikyte L, Rubin RR, Peyrot M, Gonzalez JS, Boulton AJ, Ulbrecht JS, Cavanagh PR (April 2009).

1102: 1043: 695:

1. A surface ulcer involves full skin thickness, but does not yet involve the underlying tissues.

669:

Diabetic foot ulcer is a complication of diabetes. Diabetic foot ulcers are classified as either

625: 389:

proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen,

4992:

Di Rocco G, Gentile A, Antonini A, Ceradini F, Wu JC, Capogrossi MC, Toietta G (December 2010).

5751: 5402: 5372: 5362: 5277: 5248: 5192: 3581:"Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews" 1640: 1634: 937: 853: 267:

is often considered as a 'conductor of the wound healing symphony'. In the Inflammatory phase,

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Skin grafting and tissue replacements can help to improve the healing of diabetic foot ulcer.

80:. Secondary complications to the ulcer, such as infection of the skin or subcutaneous tissue, 5550: 5545: 5339: 2315:

McLennan SV, Fisher E, Martell SY, Death AK, Williams PF, Lyons JG, Yue DK (September 2000).

915: 504: 487: 479: 475: 455: 217: 180: 156:

Risk factors implicated in the development of diabetic foot ulcers are infection, older age,

134: 2898: 2618:

Bus SA, Valk GD, van Deursen RW, Armstrong DG, Caravaggi C, Hlavácek P, et al. (2008).

573:. To mention precisely, growth factors promote switching of early inflammatory phase to the 5710: 5669: 5602: 5592: 5587: 5475: 5242: 4716:"Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections" 4322:"Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus" 2120:

Ravanti L, Kähäri VM (October 2000). "Matrix metalloproteinases in wound repair (review)".

945: 639: 541: 529: 517: 386: 373:

formation. Increased glucose levels in the body end up in uncontrolled covalent bonding of

355: 264: 259: 240: 184: 99: 65: 3261:

Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF, Cavanagh PR (January 2016).

164:, cigarette smoking, poor glycemic control, previous foot ulcerations or amputations, and 8: 5720: 5705: 5619: 5614: 5597: 5582: 5510: 5505: 5470: 5437: 5367: 5165: 762: 316: 192: 157: 3143:

Chappell FM, Crawford F, Horne M, Leese GP, Martin A, Weller D, et al. (May 2021).

1169: 1144: 1143:

Armstrong, David G.; Tan, Tze-Woei; Boulton, Andrew J. M.; Bus, Sicco A. (3 July 2023).

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in diabetic ulcers, MMP activity is known to increase by 30 fold when compared to acute

5684: 5272: 5069: 5044: 5020: 4993: 4934: 4909: 4885: 4861:"Skin grafting and tissue replacement for treating foot ulcers in people with diabetes" 4860: 4836: 4811: 4787: 4752: 4691: 4666: 4647: 4531: 4506: 4484: 4444: 4419: 4395: 4370: 4346: 4321: 4267: 4217: 4112: 4046:

Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB (June 2001).

3984: 3958:"A survey of offloading practices for diabetes-related plantar neuropathic foot ulcers" 3957: 3835: 3810: 3755: 3730: 3706: 3681: 3657: 3632: 3608: 3512: 3487: 3468: 3429: 3404: 3385: 3335: 3292: 3208: 3169: 3144: 3100: 3087: 3062: 3043: 2954: 2929: 2910: 2778: 2718: 2685: 2600: 2557: 2509: 2484: 2465: 2382: 2357: 2292: 2267: 2064: 2012: 1987: 1898: 1793:"Advanced glycation end products: sparking the development of diabetic vascular injury" 1591: 1518: 1501: 1482: 1299: 1272: 1182: 786: 574: 410: 370: 327: 299:

basement membrane also contains laminin, perlecan and nidogen. Hyaluronic acid, a pure

130: 108: 4859:

Santema TB, Poyck PP, Ubbink DT, et al. (Cochrane Wounds Group) (February 2016).

4635: 4596: 3459:(Plain English summary). National Institute for Health and Care Research. 2020-08-05. 3239: 3199:(Plain English summary). National Institute for Health and Care Research. 2022-07-26. 2418: 2168: 1809: 1792: 478:

inhibitor due to high glucose associated kidney dysfunction and reduced production of

5490: 5427: 5357: 5312: 5185: 5109: 5074: 5025: 4974: 4939: 4890: 4841: 4792: 4733: 4696: 4639: 4600: 4580: 4536: 4488: 4449: 4400: 4351: 4302: 4272: 4238:

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4221: 4209: 4174: 4143: 4104: 4069: 4028: 3989: 3938: 3911: 3870: 3840: 3791: 3760: 3711: 3662: 3613: 3561: 3517: 3472: 3434: 3389: 3377: 3355:"Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review" 3327: 3284: 3243: 3212: 3174: 3104: 3092: 3047: 2959: 2902: 2841: 2822: 2770: 2762: 2723: 2705: 2664: 2641: 2592: 2549: 2545: 2514: 2457: 2453: 2422: 2387: 2338: 2333: 2316: 2297: 2283: 2248: 2207: 2172: 2137: 2099: 2056: 2017: 1968: 1933: 1890: 1855: 1814: 1728: 1723: 1706: 1684: 1680: 1644: 1583: 1546: 1523: 1447: 1405: 1359: 1304: 1244: 1186: 1174: 1057: 1046: 904: 809: 406: 397:

through AGE-AGE intermolecular covalent bonds or cross-linking. AGE cross-linking on

366: 323: 300: 233: 103: 4651: 4116: 3339: 3296: 3028:"Simple tool identifies the people with diabetes most likely to develop foot ulcers" 2914: 2782: 2686:"Misdiagnosis of diabetic foot ulcer in patients with undiagnosed skin malignancies" 2604: 2561: 2469: 2068: 1902: 1595: 1486: 1355: 789:

supports, cushioned cut-outs around points at risk of damage, and cushioning at the

5465: 5105: 5101: 5064: 5056: 5015: 5005: 4966: 4929: 4925: 4921: 4880: 4876: 4872: 4831: 4827: 4823: 4782: 4772: 4768: 4764: 4753:"Intensive versus conventional glycaemic control for treating diabetic foot ulcers" 4728: 4723: 4715: 4686: 4682: 4678: 4631: 4592: 4526: 4522: 4518: 4476: 4439: 4435: 4431: 4390: 4386: 4382: 4341: 4337: 4333: 4262: 4258: 4254: 4201: 4170: 4166: 4139: 4135: 4096: 4059: 4020: 3979: 3969: 3901: 3830: 3826: 3822: 3787: 3783: 3750: 3746: 3742: 3701: 3697: 3693: 3652: 3648: 3644: 3603: 3599: 3595: 3551: 3507: 3503: 3499: 3460: 3424: 3416: 3369: 3319: 3274: 3262: 3235: 3200: 3164: 3156: 3082: 3074: 3035: 2949: 2945: 2941: 2894: 2818: 2814: 2754: 2713: 2697: 2631: 2584: 2541: 2504: 2496: 2449: 2414: 2377: 2369: 2328: 2287: 2279: 2238: 2199: 2164: 2129: 2091: 2048: 2007: 1999: 1960: 1929: 1925: 1882: 1845: 1804: 1718: 1676: 1575: 1513: 1474: 1439: 1397: 1351: 1294: 1284: 1164: 1156: 1086: 533: 414: 291: 225: 115: 61: 4970: 2805:

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0. No diabetic foot ulcer is present, but there is a high risk of developing one.

418: 398: 303:

component, is found in high amounts in damaged or growing tissues. It stimulates

236:

often differ chemically, but collagen generally forms the bulk of the structure.

4024: 2866: 1443: 1401: 5624: 5497: 5045:"New Molecular Techniques to Study the Skin Microbiota of Diabetic Foot Ulcers" 3862: 3488:"Topical antimicrobial agents for treating foot ulcers in people with diabetes" 3204: 3160: 3039: 1478: 1008: 857: 837: 566: 331: 4064: 4047: 3974: 2243: 2226: 2095: 474:. Reasons that have been postulated in the literature include accumulation of 279:

which in subsequent granulation phase migrate into the wound, laying down new

255:

is a localized event involving the reaction of cells to the damage sustained.

5740: 5641: 5562: 5540: 4100: 3453:"Bespoke shoes and insoles could prevent foot ulcers in people with diabetes" 2766: 2709: 1579: 1451: 1201: 1002: 933: 878: 861: 781: 777: 739: 735: 657:

discharge, unpleasant smell, sinus, undermined edges and exposure of bone or

604: 557: 463: 405:

results in increased stiffness. AGEs are also known to increase synthesis of

378: 339: 252: 248: 169: 95: 81: 77: 5060: 4812:"Nutritional interventions for treating foot ulcers in people with diabetes" 4578: 1160: 417:

in the basement membrane, reduced polymer elongation and reduced binding of

5646: 5387: 5382: 5113: 5078: 5029: 4978: 4943: 4894: 4845: 4796: 4737: 4700: 4643: 4604: 4540: 4453: 4404: 4355: 4306: 4276: 4213: 4178: 4147: 4073: 4032: 3993: 3942: 3915: 3874: 3844: 3795: 3764: 3715: 3666: 3617: 3565: 3521: 3438: 3381: 3331: 3288: 3247: 3178: 3096: 2963: 2826: 2774: 2742: 2727: 2645: 2596: 2553: 2518: 2461: 2391: 2342: 2301: 2252: 2176: 2141: 2060: 2021: 1972: 1937: 1873:

Brownlee M (1995). "Advanced protein glycosylation in diabetes and aging".

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Edwards J, Stapley S, et al. (Cochrane Wounds Group) (January 2010).

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Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY (April 2008).

2211: 2052: 1894: 1850: 1833: 1732: 1688: 434:

is known as an important stimulator of cell proliferation, maturation and

5689: 5417: 5255: 4664: 4480: 4417: 2867:"Diabetic Socks - What is a Diabetic Sock & What Socks are Available" 2133: 2103: 2003: 1289: 841: 826: 805: 790: 758: 670: 499: 390: 308: 276: 272: 268: 145: 126: 122: 3464: 1986:

Linden E, Cai W, He JC, Xue C, Li Z, Winston J, et al. (May 2008).

446:

proliferation and thereby collagen production in wound healing. Also, L-

5349: 4908:

McGloin H, Devane D, McIntosh CD, Winkley K, Gethin G (February 2021).

3538:

Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG (August 2004).

3352: 1611:"Extracellular matrix: review of its roles in acute and chronic wounds" 965: 849: 545: 443: 4777: 3373: 3279: 3078: 2701: 5392: 5160: 3420: 2636: 2619: 2588: 2373: 833: 765:

supporting the effectiveness of at-home foot temperature monitoring.

678: 570: 553: 244: 201: 188: 5143: 4369:

Liu J, Zhang P, Tian J, Li L, Li J, Tian JH, Yang K (October 2015).

4237: 2740: 5422: 5208: 4205: 3906: 3889: 3556: 3539: 896: 865: 821: 730:

Steps to prevent diabetic foot ulcers include frequent review by a

654: 650: 646: 471: 447: 347: 335: 304: 280: 197: 165: 85: 44: 4048:"Off-loading the diabetic foot wound: a randomized clinical trial" 3579:

Wu L, Norman G, Dumville JC, O'Meara S, Bell-Syer SE (July 2015).

3060: 2661:

Foot And Ankle Motion Analysis (Clinical Treatment and Technology)

520:

proteins and delayed wound contraction and impaired wound healing.

507:, numerous vesicular bodies and lack of microtubular structure in 247:) there forms a continuous association between the cell interior, 133:, and removing pressure from the wound through techniques such as 4292: 3808: 3679: 3630: 2927: 1098: 813: 718: 402: 394: 4371:"Ozone therapy for treating foot ulcers in people with diabetes" 1666: 893:

recommended that the cost of the product be taken into account.

829:

with culture is the gold standard for diagnosing osteomyelitis.

5305: 5302: 5299: 5296: 5293: 5290: 5043:

Lavigne JP, Sotto A, Dunyach-Remy C, Lipsky BA (January 2015).

4991: 4750: 4507:"Phototherapy for treating foot ulcers in people with diabetes" 4005: 4003: 3034:. National Institute for Health and Care Research. 2022-06-21. 2930:"Complex interventions for preventing diabetic foot ulceration" 1502:"Foot ulcers in the diabetic patient, prevention and treatment" 1094: 1090: 983: 900: 723: 658: 374: 221: 173: 89: 5042: 4045: 4009: 2883: 2683: 2531: 2224: 1915: 1337:"Diabetic foot ulcer management: the podiatrist's perspective" 466:. Thus, diabetic patients exhibit reduced ability to generate 4713: 4667:"Autologous platelet-rich plasma for treating chronic wounds" 4505:

Wang HT, Yuan JQ, Zhang B, Dong ML, Mao C, Hu D (June 2017).

3888:

Armstrong DG, Lavery LA, Nixon BP, Boulton AJ (August 2004).

3312:

JBI Database of Systematic Reviews and Implementation Reports

817: 326:, but in healing wounds they are up-regulated throughout the 112: 4907: 4000: 3860: 3260: 2482: 2439: 2189: 1791:

Goldin A, Beckman JA, Schmidt AM, Creager MA (August 2006).

1273:"Literature review on the management of diabetic foot ulcer" 346:. Poor wound healing in diabetes mellitus may be related to 5674: 5177: 4617: 4319: 3887: 3578: 2617: 2574: 2358:"Cellular and molecular basis of wound healing in diabetes" 2081: 1790: 229: 5091: 4086: 3809:

Dumville JC, O'Meara S, Deshpande S, Speak K (June 2013).

3680:

Dumville JC, O'Meara S, Deshpande S, Speak K (July 2013).

3631:

Dumville JC, Deshpande S, O'Meara S, Speak K (June 2013).

3537: 3485: 3403:

Collings R, Freeman J, Latour JM, Paton J (January 2021).

3402: 3142: 2314: 2154: 1270: 4956: 1704: 1089:. Investigations into characterizing and identifying the 881:. Most ulcer infections involve multiple microorganisms. 486:

observed in diabetic patients and pH dependent nature of

3123:

National Institute for Health and Care Excellence (NICE)

1636:

Wound Care:a collaborative practice manual third Edition

385:(AGEs) or Amadori products. Formation of AGEs occurs on 243:(transmitted through the anchoring molecules classed as 1745: 1499: 868:

strains), and arterial revascularization if necessary.

3225: 2265: 1992:

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1202:"Protective and Damaging Aspects of Healing: A Review" 1142: 4194:

Journal of the American Podiatric Medical Association

4013:

Journal of the American Podiatric Medical Association

3811:"Alginate dressings for healing diabetic foot ulcers" 3682:"Hydrogel dressings for healing diabetic foot ulcers" 3309: 1832:

Singh R, Barden A, Mori T, Beilin L (February 2001).

1831: 960:

concluded that for people with diabetic foot ulcers,

228:, and these two layers are collectively known as the 5133: 1608: 4809: 4466: 3869:. Agency for Healthcare Research and Quality (US). 3193:"Diabetes: putting people at the heart of services" 3119:"Diabetic foot problems: prevention and management" 3007:"Amputation and diabetes: How to protect your feet" 2037: 1543:

Cell biology of extracellular matrix second edition

4858: 4420:"Growth factors for treating diabetic foot ulcers" 1500:Wu SC, Driver VR, Wrobel JS, Armstrong DG (2007). 971: 525:Increased matrix metalloproteinases (MMP) activity 191:dysfunction and dryness of the skin. Blisters and 121:Treatment of diabetic foot ulcers should include: 4504: 4191: 3928: 3633:"Foam dressings for healing diabetic foot ulcers" 2743:"Melanoma masquerading as nonmelanocytic lesions" 148:associated with a diabetic foot ulcer formation. 5738: 5408:Metabolic Score for Insulin Resistance (METS-IR) 5036: 1950: 1138: 1136: 1134: 1132: 1130: 1128: 1126: 1124: 1122: 628:, whose analysis is not part of this discussion. 495:Structural and functional changes in fibroblasts 377:sugars to a protein or lipid without any normal 3955: 2800: 2798: 2796: 2794: 2792: 2355: 1199: 734:and multidisciplinary team, good foot hygiene, 413:. AGEs on laminin result in reduced binding to 4368: 4240:"Hyperbaric oxygen therapy for chronic wounds" 3728: 3533: 3531: 2842:"Diabetic Ulcers: Everything You Need to Know" 2404: 2033: 2031: 1985: 1639:. Lippincott Williams & Wilkins. pp. 1430:Boulton AJ (2019-02-01). "The diabetic foot". 1383: 1381: 1379: 1377: 1375: 1373: 1330: 1328: 1326: 1324: 1322: 1320: 1318: 137:. Surgery in some cases may improve outcomes. 5193: 4810:Moore ZE, Corcoran MA, Patton D (July 2020). 4233: 4231: 3777: 2119: 1764: 1119: 726:closures for ease of application and removal. 544:components. They are known to be involved in 5085: 4288: 4286: 4123: 4039: 3949: 2789: 2611: 2476: 757:A common method for this is using a special 748: 92:are possible, often leading to amputation. 4914:The Cochrane Database of Systematic Reviews 4865:The Cochrane Database of Systematic Reviews 4816:The Cochrane Database of Systematic Reviews 4757:The Cochrane Database of Systematic Reviews 4720:The Cochrane Database of Systematic Reviews 4671:The Cochrane Database of Systematic Reviews 4511:The Cochrane Database of Systematic Reviews 4424:The Cochrane Database of Systematic Reviews 4375:The Cochrane Database of Systematic Reviews 4326:The Cochrane Database of Systematic Reviews 4247:The Cochrane Database of Systematic Reviews 4163:The Cochrane Database of Systematic Reviews 4132:The Cochrane Database of Systematic Reviews 3856: 3854: 3815:The Cochrane Database of Systematic Reviews 3780:The Cochrane Database of Systematic Reviews 3735:The Cochrane Database of Systematic Reviews 3686:The Cochrane Database of Systematic Reviews 3637:The Cochrane Database of Systematic Reviews 3588:The Cochrane Database of Systematic Reviews 3528: 3492:The Cochrane Database of Systematic Reviews 2934:The Cochrane Database of Systematic Reviews 2877: 2122:International Journal of Molecular Medicine 2028: 1834:"Advanced glycation end-products: a review" 1370: 1315: 649:, condition of the border of the wound and 239:Through the interaction of a cell with its 5200: 5186: 4228: 3540:"Wound dressings in diabetic foot disease" 2115: 2113: 1628: 1626: 1624: 1458: 1223: 1221: 1219: 688:Wagner Grades 0 through 5 are as follows: 603:effects on tendons and ligaments: protein 27: 5094:Journal of Diabetes and Its Complications 5068: 5019: 5009: 4933: 4884: 4835: 4786: 4776: 4727: 4690: 4530: 4443: 4394: 4345: 4283: 4266: 4160: 4129: 4063: 3983: 3973: 3905: 3834: 3754: 3705: 3656: 3607: 3555: 3511: 3428: 3278: 3168: 3086: 2953: 2717: 2635: 2508: 2433: 2381: 2332: 2291: 2242: 2011: 1849: 1808: 1786: 1784: 1782: 1780: 1722: 1700: 1698: 1669:Journal of Oral and Maxillofacial Surgery 1662: 1660: 1517: 1298: 1288: 1266: 1264: 1168: 4624:The Lancet. Diabetes & Endocrinology 4585:The Lancet. Diabetes & Endocrinology 3851: 3409:Endocrinology, Diabetes & Metabolism 3362:Diabetes/Metabolism Research and Reviews 3267:Diabetes/Metabolism Research and Reviews 3067:Diabetes/Metabolism Research and Reviews 2624:Diabetes/Metabolism Research and Reviews 2577:Diabetes/Metabolism Research and Reviews 2192:The Journal of Investigative Dermatology 1872: 1866: 1711:The Journal of Investigative Dermatology 1609:Schultz GS, Ludwig G, Wysocki A (2005). 1559: 1545:. New York: Plenum press. pp. 1–5. 1227: 948:) and Cutimed Off-loader (BSN Medical). 910: 903:have not been properly studied nor have 717: 286:In the initial events of wound healing, 4959:Diabetes Research and Clinical Practice 4555:"Wound healing interventions guideline" 3624: 2899:10.7326/0003-4819-119-1-199307010-00006 2489:The British Journal of General Practice 2183: 2148: 2110: 1758: 1739: 1632: 1621: 1602: 1429: 1216: 1200:Nomikos Iakovos N, et al. (2006). 212: 5739: 2658: 2398: 2349: 2259: 2218: 1979: 1777: 1695: 1657: 1261: 1193: 5181: 4500: 4498: 3731:"Debridement of diabetic foot ulcers" 3149:BMJ Open Diabetes Research & Care 3022: 3020: 2804: 2362:The Journal of Clinical Investigation 2308: 1825: 1464: 1387: 1334: 1034:granulocyte colony-stimulating factor 361: 127:removal of dead tissue from the wound 5450:Metabolic assessment and monitoring 2839: 2663:. USA: CRC Press. pp. 317–401. 2075: 1425: 1423: 1421: 1419: 1390:British Journal of Community Nursing 1344:British Journal of Community Nursing 1230:"Molecular aspects of wound healing" 951: 540:are known to degrade almost all the 5726:Notable people with type 1 diabetes 5238:(SIDD, SIRD, MOD and MARD clusters) 2041:Archives of Dermatological Research 1944: 1909: 1540: 1506:Vascular Health and Risk Management 997: 13: 4495: 3962:Journal of Foot and Ankle Research 3017: 2356:Brem H, Tomic-Canic M (May 2007). 887: 207: 14: 5763: 5680:International Diabetes Federation 3240:10.2174/1573399810666140918121438 1918:Journal of Dermatological Science 1810:10.1161/CIRCULATIONAHA.106.621854 1493: 1416: 844:, appropriate bandages, managing 664: 352:post-transcriptional modification 74:complication of diabetes mellitus 5556:Hyperosmolar hyperglycemic state 2546:10.1111/j.1464-5491.2008.02573.x 2454:10.1111/j.1743-6109.2006.00155.x 2334:10.1046/j.1523-1755.2000.07713.x 2284:10.1111/j.1464-5491.2008.02414.x 1724:10.1046/j.1523-1747.1998.00381.x 1228:McLennan S, et al. (2006). 1145:"Diabetic Foot Ulcers: A Review" 509:transmission electron microscopy 334:is clearly an important role of 141:may also help but is expensive. 4985: 4950: 4901: 4852: 4803: 4744: 4707: 4658: 4611: 4572: 4547: 4460: 4411: 4362: 4313: 4185: 4154: 4080: 3956:Raspovic A, Landorf KB (2014). 3922: 3881: 3867:Data Points Publication Series 3802: 3771: 3722: 3673: 3572: 3479: 3445: 3396: 3346: 3303: 3254: 3219: 3185: 3136: 3111: 3054: 2999: 2970: 2921: 2859: 2833: 2734: 2677: 2652: 2568: 2525: 1534: 1356:10.12968/bjcn.2013.18.Sup12.S14 1063: 1032:There is limited evidence that 988:negative pressure wound therapy 978:Negative pressure wound therapy 972:Negative pressure wound therapy 616:(reduction of muscle strength); 582: 151: 36:Neuropathic diabetic foot ulcer 5106:10.1016/j.jdiacomp.2018.01.015 4926:10.1002/14651858.cd012835.pub2 4877:10.1002/14651858.CD011255.pub2 4828:10.1002/14651858.cd011378.pub2 4769:10.1002/14651858.CD010764.pub2 4729:10.1002/14651858.CD006810.pub3 4683:10.1002/14651858.CD006899.pub3 4523:10.1002/14651858.CD011979.pub2 4436:10.1002/14651858.CD008548.pub2 4387:10.1002/14651858.CD008474.pub2 4338:10.1002/14651858.CD010318.pub3 4259:10.1002/14651858.CD004123.pub4 4171:10.1002/14651858.CD002302.pub2 4140:10.1002/14651858.CD002302.pub2 3827:10.1002/14651858.CD009110.pub3 3788:10.1002/14651858.CD005082.pub2 3747:10.1002/14651858.CD003556.pub2 3698:10.1002/14651858.CD009101.pub3 3649:10.1002/14651858.CD009111.pub3 3600:10.1002/14651858.CD010471.pub2 3504:10.1002/14651858.CD011038.pub2 2946:10.1002/14651858.CD007610.pub3 2819:10.12968/bjon.2011.20.Sup8.S19 1930:10.1016/j.jdermsci.2005.08.004 871: 620:processes or tissue breakdown; 528:In order for a wound to heal, 462:, which plays a major role in 383:advanced glycation endproducts 1: 5615:Diabetes-related skin disease 4971:10.1016/j.diabres.2011.10.032 4636:10.1016/S2213-8587(18)30240-7 4597:10.1016/S2213-8587(17)30438-2 2982:American Diabetes Association 2442:Wound Repair and Regeneration 2419:10.1016/s0002-9610(05)80589-6 2169:10.1016/s0046-8177(99)90140-5 1112: 929:method for off-loading DFUs. 713: 258:The cells break down damaged 58:peripheral sensory neuropathy 5413:Homeostatic model assessment 5207: 3894:Clinical Infectious Diseases 3544:Clinical Infectious Diseases 3324:10.11124/JBISRIR-2016-003013 2759:10.1097/CMR.0000000000000294 2204:10.1111/1523-1747.ep12359590 1965:10.1016/j.molmed.2004.02.001 1953:Trends in Molecular Medicine 1887:10.1146/annurev.med.46.1.223 1681:10.1016/0278-2391(95)90721-1 1467:Osteopathic Family Physician 944:TCC systems include TCC-EZ ( 840:. The treatment consists of 799: 632: 565:a wide variety of different 111:and a parallel reduction in 7: 5398:Noninvasive glucose monitor 4025:10.7547/8750-7315-104.6.555 2887:Annals of Internal Medicine 2690:International Wound Journal 2407:American Journal of Surgery 1444:10.1016/j.mpmed.2018.11.001 1402:10.12968/bjcn.2012.17.9.422 1080: 846:peripheral arterial disease 812:, diabetes specialists and 772: 283:of the subtypes I and III. 162:peripheral vascular disease 70:peripheral arterial disease 62:peripheral motor neuropathy 10: 5768: 5630:Diabetic cheiroarthropathy 5459:Ambulatory glucose profile 5266:Impaired glucose tolerance 3205:10.3310/nihrevidence_52026 3161:10.1136/bmjdrc-2021-002150 3040:10.3310/nihrevidence_51316 2807:British Journal of Nursing 1479:10.1016/j.osfp.2012.08.002 975: 562:Transforming growth factor 5747:Complications of diabetes 5698: 5655: 5531: 5436: 5378:Postprandial glucose test 5348: 5215: 5151: 5137: 4065:10.2337/diacare.24.6.1019 3975:10.1186/s13047-014-0035-8 2244:10.1007/s00125-002-0868-8 2096:10.2337/diabetes.26.4.284 1875:Annual Review of Medicine 1396:(9): 422, 424–27, 430–3. 1335:Turns M (December 2013). 1277:World Journal of Diabetes 1243:(1): 8–13. Archived from 962:hyperbaric oxygen therapy 749:Monitoring and prediction 722:Many diabetic shoes have 538:matrix metalloproteinases 139:Hyperbaric oxygen therapy 40: 35: 26: 21: 5716:Epidemiology of diabetes 5454:Blood glucose monitoring 5330:Type 3c (pancreatogenic) 5261:Impaired fasting glucose 4998:Stem Cells International 4101:10.2337/diacare.19.8.818 3550:(Supplement 2): S100-3. 3228:Current Diabetes Reviews 2840:Hamilton R, Hamilton J. 1580:10.1177/0145721706286897 5573:Neuropathic arthropathy 5061:10.1089/wound.2014.0532 4295:Ostomy/Wound Management 3931:Ostomy/Wound Management 1161:10.1001/jama.2023.10578 848:and appropriate use of 626:neuropathic arthropathy 322:is mainly found in the 5521:Gastric bypass surgery 5403:Insulin tolerance test 5373:Glucose tolerance test 5278:Ketosis-prone diabetes 5249:Diabetes and pregnancy 5049:Advances in Wound Care 1103:nonpathogenic bacteria 938:Cochrane Collaboration 854:pseudomonas aeruginosa 727: 76:, and it is a type of 2501:10.3399/bjgp09X420383 2053:10.1007/s004030050389 1851:10.1007/s001250051591 1568:The Diabetes Educator 916:Total contact casting 911:Total contact casting 721: 505:endoplasmic reticulum 488:nitric oxide synthase 480:nitric oxide synthase 476:nitric oxide synthase 456:nitric oxide synthase 428:Impaired NO synthesis 275:recruit and activate 218:Extra cellular matrix 181:Peripheral neuropathy 135:total contact casting 78:diabetic foot disease 5711:Glossary of diabetes 5670:Open Insulin Project 5506:Embryonic stem cells 5243:Gestational diabetes 4481:10.1557/mrc.2018.181 2630:(Suppl 1): S162-80. 2321:Kidney International 2134:10.3892/ijmm.6.4.391 2004:10.2215/CJN.04291007 1290:10.4239/wjd.v6.i1.37 982:This treatment uses 964:reduced the risk of 946:Integra LifeSciences 640:alcohol use disorder 542:extracellular matrix 536:. Proteases, namely 530:extracellular matrix 518:extracellular matrix 387:extracellular matrix 356:extracellular matrix 265:extracellular matrix 241:extracellular matrix 213:Extracellular matrix 185:Autonomic neuropathy 100:extracellular matrix 66:autonomic neuropathy 5721:History of diabetes 5706:Outline of diabetes 5635:Diabetic foot ulcer 5620:Diabetic dermopathy 5579:Organs in diabetes 5511:Artificial pancreas 5471:Diabetes medication 5368:Glycated hemoglobin 5011:10.4061/2011/304562 3465:10.3310/alert_40657 3273:(Suppl 1): 99–118. 2583:(Suppl 1): S192-3. 763:scientific evidence 317:chondroitin sulfate 158:diabetic neuropathy 53:Diabetic foot ulcer 22:Diabetic foot ulcer 5685:World Diabetes Day 5273:Insulin resistance 5152:External resources 4469:MRS Communications 3900:(Suppl 2): S92-9. 3368:(Suppl 1): e3270. 2846:Healing Your Wound 2495:(561): 290.1–290. 1633:Sussman C (2006). 905:alginate dressings 728: 575:granulation tissue 411:granulation tissue 371:granulation tissue 362:Altered metabolism 328:granulation tissue 311:and thus promotes 234:connective tissues 109:granulation tissue 5734: 5733: 5428:Disposition index 5358:Blood sugar level 5228:Type 1 diabetes ( 5175: 5174: 5130: 3374:10.1002/dmrr.3270 3280:10.1002/dmrr.2702 3079:10.1002/dmrr.3549 2747:Melanoma Research 2702:10.1111/iwj.13688 2670:978-0-8493-3971-4 2534:Diabetic Medicine 2272:Diabetic Medicine 1767:The Diabetic Foot 1650:978-0-7817-7444-4 1615:World Wide Wounds 1552:978-0-306-40785-7 1237:Primary Intention 1058:systematic review 1047:systematic review 952:Hyperbaric oxygen 810:vascular surgeons 598:autonomic nervous 407:type III collagen 367:Diabetes mellitus 324:basement membrane 315:. In normal skin 301:glycosaminoglycan 104:Diabetes mellitus 72:. It is a major 50: 49: 16:Medical condition 5759: 5466:Diet in diabetes 5202: 5195: 5188: 5179: 5178: 5135: 5134: 5125: 5118: 5117: 5089: 5083: 5082: 5072: 5040: 5034: 5033: 5023: 5013: 4989: 4983: 4982: 4954: 4948: 4947: 4937: 4905: 4899: 4898: 4888: 4856: 4850: 4849: 4839: 4807: 4801: 4800: 4790: 4780: 4748: 4742: 4741: 4731: 4711: 4705: 4704: 4694: 4662: 4656: 4655: 4615: 4609: 4608: 4576: 4570: 4569: 4567: 4566: 4559:IWGDF Guidelines 4551: 4545: 4544: 4534: 4502: 4493: 4492: 4475:(3): 1184–1190. 4464: 4458: 4457: 4447: 4430:(10): CD008548. 4415: 4409: 4408: 4398: 4381:(10): CD008474. 4366: 4360: 4359: 4349: 4332:(10): CD010318. 4317: 4311: 4310: 4290: 4281: 4280: 4270: 4244: 4235: 4226: 4225: 4189: 4183: 4182: 4158: 4152: 4151: 4127: 4121: 4120: 4084: 4078: 4077: 4067: 4043: 4037: 4036: 4007: 3998: 3997: 3987: 3977: 3953: 3947: 3946: 3926: 3920: 3919: 3909: 3885: 3879: 3878: 3858: 3849: 3848: 3838: 3806: 3800: 3799: 3775: 3769: 3768: 3758: 3726: 3720: 3719: 3709: 3677: 3671: 3670: 3660: 3628: 3622: 3621: 3611: 3585: 3576: 3570: 3569: 3559: 3535: 3526: 3525: 3515: 3483: 3477: 3476: 3449: 3443: 3442: 3432: 3421:10.1002/edm2.132 3400: 3394: 3393: 3359: 3350: 3344: 3343: 3307: 3301: 3300: 3282: 3258: 3252: 3251: 3223: 3217: 3216: 3189: 3183: 3182: 3172: 3140: 3134: 3133: 3131: 3130: 3125:. 26 August 2015 3115: 3109: 3108: 3090: 3058: 3052: 3051: 3024: 3015: 3014: 3003: 2997: 2996: 2994: 2993: 2984:. Archived from 2974: 2968: 2967: 2957: 2925: 2919: 2918: 2881: 2875: 2874: 2863: 2857: 2856: 2854: 2852: 2837: 2831: 2830: 2802: 2787: 2786: 2738: 2732: 2731: 2721: 2681: 2675: 2674: 2656: 2650: 2649: 2639: 2637:10.1002/dmrr.850 2615: 2609: 2608: 2589:10.1002/dmrr.855 2572: 2566: 2565: 2529: 2523: 2522: 2512: 2480: 2474: 2473: 2437: 2431: 2430: 2402: 2396: 2395: 2385: 2374:10.1172/JCI32169 2353: 2347: 2346: 2336: 2312: 2306: 2305: 2295: 2263: 2257: 2256: 2246: 2222: 2216: 2215: 2187: 2181: 2180: 2152: 2146: 2145: 2117: 2108: 2107: 2079: 2073: 2072: 2035: 2026: 2025: 2015: 1983: 1977: 1976: 1948: 1942: 1941: 1913: 1907: 1906: 1870: 1864: 1863: 1853: 1829: 1823: 1822: 1812: 1788: 1775: 1774: 1762: 1756: 1755: 1754: 1750: 1743: 1737: 1736: 1726: 1702: 1693: 1692: 1664: 1655: 1654: 1630: 1619: 1618: 1606: 1600: 1599: 1563: 1557: 1556: 1538: 1532: 1531: 1521: 1497: 1491: 1490: 1462: 1456: 1455: 1427: 1414: 1413: 1385: 1368: 1367: 1341: 1332: 1313: 1312: 1302: 1292: 1268: 1259: 1258: 1256: 1255: 1249: 1234: 1225: 1214: 1213: 1197: 1191: 1190: 1172: 1140: 998:Other treatments 791:ball of the foot 534:tensile strength 415:type IV collagen 292:tensile strength 116:tensile strength 31: 19: 18: 5767: 5766: 5762: 5761: 5760: 5758: 5757: 5756: 5737: 5736: 5735: 5730: 5694: 5665:T1International 5657: 5656:Advocacy & 5651: 5527: 5476:Insulin therapy 5432: 5344: 5211: 5206: 5176: 5171: 5170: 5147: 5146: 5122: 5121: 5090: 5086: 5041: 5037: 4990: 4986: 4955: 4951: 4920:(2): CD012835. 4906: 4902: 4871:(3): CD011255. 4857: 4853: 4822:(7): CD011378. 4808: 4804: 4763:(1): CD010764. 4749: 4745: 4722:(8): CD006810. 4712: 4708: 4677:(5): CD006899. 4663: 4659: 4630:(11): 870–878. 4616: 4612: 4577: 4573: 4564: 4562: 4553: 4552: 4548: 4517:(6): CD011979. 4503: 4496: 4465: 4461: 4416: 4412: 4367: 4363: 4318: 4314: 4291: 4284: 4253:(6): CD004123. 4242: 4236: 4229: 4190: 4186: 4165:(1): CD002302. 4159: 4155: 4134:(1): CD002302. 4128: 4124: 4085: 4081: 4044: 4040: 4008: 4001: 3954: 3950: 3927: 3923: 3886: 3882: 3859: 3852: 3821:(6): CD009110. 3807: 3803: 3782:(1): CD005082. 3776: 3772: 3741:(1): CD003556. 3727: 3723: 3692:(7): CD009101. 3678: 3674: 3643:(6): CD009111. 3629: 3625: 3594:(7): CD010471. 3583: 3577: 3573: 3536: 3529: 3498:(6): CD011038. 3484: 3480: 3451: 3450: 3446: 3401: 3397: 3357: 3351: 3347: 3308: 3304: 3259: 3255: 3224: 3220: 3191: 3190: 3186: 3141: 3137: 3128: 3126: 3117: 3116: 3112: 3059: 3055: 3026: 3025: 3018: 3005: 3004: 3000: 2991: 2989: 2976: 2975: 2971: 2940:(8): CD007610. 2926: 2922: 2882: 2878: 2865: 2864: 2860: 2850: 2848: 2838: 2834: 2803: 2790: 2739: 2735: 2682: 2678: 2671: 2657: 2653: 2616: 2612: 2573: 2569: 2530: 2526: 2485:"Diabetic feet" 2481: 2477: 2438: 2434: 2403: 2399: 2354: 2350: 2313: 2309: 2264: 2260: 2223: 2219: 2188: 2184: 2157:Human Pathology 2153: 2149: 2118: 2111: 2080: 2076: 2036: 2029: 1984: 1980: 1949: 1945: 1914: 1910: 1871: 1867: 1830: 1826: 1789: 1778: 1763: 1759: 1752: 1744: 1740: 1703: 1696: 1665: 1658: 1651: 1631: 1622: 1607: 1603: 1564: 1560: 1553: 1539: 1535: 1498: 1494: 1463: 1459: 1428: 1417: 1386: 1371: 1339: 1333: 1316: 1269: 1262: 1253: 1251: 1247: 1232: 1226: 1217: 1198: 1194: 1141: 1120: 1115: 1083: 1071:quality of life 1066: 1000: 980: 974: 958:Cochrane review 954: 913: 890: 888:Wound dressings 874: 802: 775: 751: 732:foot specialist 716: 667: 635: 585: 498:Diabetic ulcer 436:differentiation 419:heparan sulfate 409:that forms the 399:type I collagen 364: 224:lies below the 215: 210: 208:Pathophysiology 154: 131:wound dressings 17: 12: 11: 5: 5765: 5755: 5754: 5749: 5732: 5731: 5729: 5728: 5723: 5718: 5713: 5708: 5702: 5700: 5696: 5695: 5693: 5692: 5687: 5682: 5677: 5672: 5667: 5661: 5659: 5653: 5652: 5650: 5649: 5644: 5639: 5638: 5637: 5632: 5627: 5625:Diabetic bulla 5622: 5612: 5611: 5610: 5605: 5600: 5595: 5590: 5585: 5577: 5576: 5575: 5570: 5560: 5559: 5558: 5553: 5548: 5541:Diabetic comas 5537: 5535: 5529: 5528: 5526: 5525: 5524: 5523: 5515: 5514: 5513: 5508: 5500: 5498:Diabetic shoes 5495: 5494: 5493: 5488: 5483: 5473: 5468: 5463: 5462: 5461: 5456: 5448: 5442: 5440: 5434: 5433: 5431: 5430: 5425: 5420: 5415: 5410: 5405: 5400: 5395: 5390: 5385: 5380: 5375: 5370: 5365: 5360: 5354: 5352: 5346: 5345: 5343: 5342: 5337: 5332: 5327: 5326: 5325: 5320: 5310: 5309: 5308: 5281: 5275: 5270: 5269: 5268: 5263: 5253: 5252: 5251: 5239: 5233: 5226: 5225:(SAID cluster) 5219: 5217: 5213: 5212: 5205: 5204: 5197: 5190: 5182: 5173: 5172: 5169: 5168: 5166:article/460282 5156: 5155: 5153: 5149: 5148: 5142: 5141: 5139: 5138:Classification 5131:External links 5120: 5119: 5100:(5): 524–530. 5084: 5035: 4984: 4949: 4900: 4851: 4802: 4743: 4706: 4657: 4610: 4591:(3): 186–196. 4571: 4546: 4494: 4459: 4410: 4361: 4312: 4282: 4227: 4206:10.7547/17-222 4200:(6): 445–450. 4184: 4153: 4122: 4079: 4058:(6): 1019–22. 4038: 3999: 3948: 3921: 3907:10.1086/383269 3880: 3850: 3801: 3770: 3721: 3672: 3623: 3571: 3557:10.1086/383270 3527: 3478: 3444: 3395: 3345: 3318:(7): 236–265. 3302: 3253: 3234:(4): 215–230. 3218: 3184: 3155:(1): e002150. 3135: 3110: 3053: 3016: 2998: 2969: 2920: 2876: 2871:Diabetes.co.uk 2858: 2832: 2813:(15): S19-25. 2788: 2753:(6): 631–634. 2733: 2696:(4): 871–887. 2676: 2669: 2651: 2610: 2567: 2540:(12): 1380–9. 2524: 2475: 2432: 2397: 2368:(5): 1219–22. 2348: 2307: 2258: 2217: 2182: 2163:(7): 795–802. 2147: 2128:(4): 391–407. 2109: 2074: 2027: 1978: 1943: 1908: 1865: 1824: 1803:(6): 597–605. 1776: 1757: 1738: 1694: 1656: 1649: 1620: 1601: 1574:(2): 197–210. 1558: 1551: 1541:Hay E (1991). 1533: 1492: 1457: 1438:(2): 100–105. 1415: 1369: 1350:: S14, S16-9. 1314: 1260: 1215: 1192: 1117: 1116: 1114: 1111: 1082: 1079: 1065: 1062: 1009:Growth factors 999: 996: 976:Main article: 973: 970: 953: 950: 912: 909: 889: 886: 873: 870: 858:staphylococcus 838:staphylococcus 801: 798: 780:, insoles and 778:Diabetic shoes 774: 771: 750: 747: 736:diabetic socks 715: 712: 709: 708: 705: 702: 699: 696: 693: 675:neuroischaemic 666: 665:Classification 663: 634: 631: 630: 629: 621: 617: 613: 609: 601: 584: 581: 580: 579: 567:growth factors 526: 522: 521: 496: 492: 491: 429: 363: 360: 332:growth factors 307:production by 214: 211: 209: 206: 153: 150: 82:bone infection 48: 47: 42: 38: 37: 33: 32: 24: 23: 15: 9: 6: 4: 3: 2: 5764: 5753: 5752:Foot diseases 5750: 5748: 5745: 5744: 5742: 5727: 5724: 5722: 5719: 5717: 5714: 5712: 5709: 5707: 5704: 5703: 5701: 5697: 5691: 5688: 5686: 5683: 5681: 5678: 5676: 5673: 5671: 5668: 5666: 5663: 5662: 5660: 5658:Organizations 5654: 5648: 5645: 5643: 5642:Hyperglycemia 5640: 5636: 5633: 5631: 5628: 5626: 5623: 5621: 5618: 5617: 5616: 5613: 5609: 5606: 5604: 5601: 5599: 5596: 5594: 5591: 5589: 5586: 5584: 5583:Blood vessels 5581: 5580: 5578: 5574: 5571: 5569: 5566: 5565: 5564: 5563:Diabetic foot 5561: 5557: 5554: 5552: 5549: 5547: 5544: 5543: 5542: 5539: 5538: 5536: 5534: 5533:Complications 5530: 5522: 5519: 5518: 5516: 5512: 5509: 5507: 5504: 5503: 5501: 5499: 5496: 5492: 5489: 5487: 5484: 5482: 5479: 5478: 5477: 5474: 5472: 5469: 5467: 5464: 5460: 5457: 5455: 5452: 5451: 5449: 5447: 5444: 5443: 5441: 5439: 5435: 5429: 5426: 5424: 5421: 5419: 5416: 5414: 5411: 5409: 5406: 5404: 5401: 5399: 5396: 5394: 5391: 5389: 5386: 5384: 5381: 5379: 5376: 5374: 5371: 5369: 5366: 5364: 5361: 5359: 5356: 5355: 5353: 5351: 5347: 5341: 5338: 5336: 5333: 5331: 5328: 5324: 5321: 5319: 5316: 5315: 5314: 5311: 5307: 5304: 5301: 5298: 5295: 5292: 5289: 5288: 5286: 5282: 5279: 5276: 5274: 5271: 5267: 5264: 5262: 5259: 5258: 5257: 5254: 5250: 5247: 5246: 5244: 5240: 5237: 5234: 5231: 5227: 5224: 5221: 5220: 5218: 5214: 5210: 5203: 5198: 5196: 5191: 5189: 5184: 5183: 5180: 5167: 5163: 5162: 5158: 5157: 5154: 5150: 5145: 5140: 5136: 5132: 5129: 5126:Jayesh Kakar 5115: 5111: 5107: 5103: 5099: 5095: 5088: 5080: 5076: 5071: 5066: 5062: 5058: 5054: 5050: 5046: 5039: 5031: 5027: 5022: 5017: 5012: 5007: 5003: 4999: 4995: 4988: 4980: 4976: 4972: 4968: 4964: 4960: 4953: 4945: 4941: 4936: 4931: 4927: 4923: 4919: 4915: 4911: 4904: 4896: 4892: 4887: 4882: 4878: 4874: 4870: 4866: 4862: 4855: 4847: 4843: 4838: 4833: 4829: 4825: 4821: 4817: 4813: 4806: 4798: 4794: 4789: 4784: 4779: 4774: 4770: 4766: 4762: 4758: 4754: 4747: 4739: 4735: 4730: 4725: 4721: 4717: 4710: 4702: 4698: 4693: 4688: 4684: 4680: 4676: 4672: 4668: 4661: 4653: 4649: 4645: 4641: 4637: 4633: 4629: 4625: 4621: 4614: 4606: 4602: 4598: 4594: 4590: 4586: 4582: 4575: 4560: 4556: 4550: 4542: 4538: 4533: 4528: 4524: 4520: 4516: 4512: 4508: 4501: 4499: 4490: 4486: 4482: 4478: 4474: 4470: 4463: 4455: 4451: 4446: 4441: 4437: 4433: 4429: 4425: 4421: 4414: 4406: 4402: 4397: 4392: 4388: 4384: 4380: 4376: 4372: 4365: 4357: 4353: 4348: 4343: 4339: 4335: 4331: 4327: 4323: 4316: 4308: 4304: 4300: 4296: 4289: 4287: 4278: 4274: 4269: 4264: 4260: 4256: 4252: 4248: 4241: 4234: 4232: 4223: 4219: 4215: 4211: 4207: 4203: 4199: 4195: 4188: 4180: 4176: 4172: 4168: 4164: 4157: 4149: 4145: 4141: 4137: 4133: 4126: 4118: 4114: 4110: 4106: 4102: 4098: 4095:(8): 818–21. 4094: 4090: 4089:Diabetes Care 4083: 4075: 4071: 4066: 4061: 4057: 4053: 4052:Diabetes Care 4049: 4042: 4034: 4030: 4026: 4022: 4019:(6): 555–67. 4018: 4014: 4006: 4004: 3995: 3991: 3986: 3981: 3976: 3971: 3967: 3963: 3959: 3952: 3944: 3940: 3936: 3932: 3925: 3917: 3913: 3908: 3903: 3899: 3895: 3891: 3884: 3876: 3872: 3868: 3864: 3857: 3855: 3846: 3842: 3837: 3832: 3828: 3824: 3820: 3816: 3812: 3805: 3797: 3793: 3789: 3785: 3781: 3774: 3766: 3762: 3757: 3752: 3748: 3744: 3740: 3736: 3732: 3725: 3717: 3713: 3708: 3703: 3699: 3695: 3691: 3687: 3683: 3676: 3668: 3664: 3659: 3654: 3650: 3646: 3642: 3638: 3634: 3627: 3619: 3615: 3610: 3605: 3601: 3597: 3593: 3589: 3582: 3575: 3567: 3563: 3558: 3553: 3549: 3545: 3541: 3534: 3532: 3523: 3519: 3514: 3509: 3505: 3501: 3497: 3493: 3489: 3482: 3474: 3470: 3466: 3462: 3458: 3457:NIHR Evidence 3454: 3448: 3440: 3436: 3431: 3426: 3422: 3418: 3415:(1): e00132. 3414: 3410: 3406: 3399: 3391: 3387: 3383: 3379: 3375: 3371: 3367: 3363: 3356: 3349: 3341: 3337: 3333: 3329: 3325: 3321: 3317: 3313: 3306: 3298: 3294: 3290: 3286: 3281: 3276: 3272: 3268: 3264: 3257: 3249: 3245: 3241: 3237: 3233: 3229: 3222: 3214: 3210: 3206: 3202: 3198: 3197:NIHR Evidence 3194: 3188: 3180: 3176: 3171: 3166: 3162: 3158: 3154: 3150: 3146: 3139: 3124: 3120: 3114: 3106: 3102: 3098: 3094: 3089: 3084: 3080: 3076: 3072: 3068: 3064: 3057: 3049: 3045: 3041: 3037: 3033: 3032:NIHR Evidence 3029: 3023: 3021: 3012: 3008: 3002: 2988:on 2015-07-07 2987: 2983: 2979: 2973: 2965: 2961: 2956: 2951: 2947: 2943: 2939: 2935: 2931: 2924: 2916: 2912: 2908: 2904: 2900: 2896: 2892: 2888: 2880: 2873:. 2019-01-15. 2872: 2868: 2862: 2847: 2843: 2836: 2828: 2824: 2820: 2816: 2812: 2808: 2801: 2799: 2797: 2795: 2793: 2784: 2780: 2776: 2772: 2768: 2764: 2760: 2756: 2752: 2748: 2744: 2737: 2729: 2725: 2720: 2715: 2711: 2707: 2703: 2699: 2695: 2691: 2687: 2680: 2672: 2666: 2662: 2655: 2647: 2643: 2638: 2633: 2629: 2625: 2621: 2614: 2606: 2602: 2598: 2594: 2590: 2586: 2582: 2578: 2571: 2563: 2559: 2555: 2551: 2547: 2543: 2539: 2535: 2528: 2520: 2516: 2511: 2506: 2502: 2498: 2494: 2490: 2486: 2479: 2471: 2467: 2463: 2459: 2455: 2451: 2448:(5): 558–65. 2447: 2443: 2436: 2428: 2424: 2420: 2416: 2412: 2408: 2401: 2393: 2389: 2384: 2379: 2375: 2371: 2367: 2363: 2359: 2352: 2344: 2340: 2335: 2330: 2326: 2322: 2318: 2311: 2303: 2299: 2294: 2289: 2285: 2281: 2278:(4): 419–26. 2277: 2273: 2269: 2262: 2254: 2250: 2245: 2240: 2237:(7): 1011–6. 2236: 2232: 2228: 2221: 2213: 2209: 2205: 2201: 2197: 2193: 2186: 2178: 2174: 2170: 2166: 2162: 2158: 2151: 2143: 2139: 2135: 2131: 2127: 2123: 2116: 2114: 2105: 2101: 2097: 2093: 2090:(4): 284–90. 2089: 2085: 2078: 2070: 2066: 2062: 2058: 2054: 2050: 2047:(2–3): 93–9. 2046: 2042: 2034: 2032: 2023: 2019: 2014: 2009: 2005: 2001: 1997: 1993: 1989: 1982: 1974: 1970: 1966: 1962: 1958: 1954: 1947: 1939: 1935: 1931: 1927: 1923: 1919: 1912: 1904: 1900: 1896: 1892: 1888: 1884: 1880: 1876: 1869: 1861: 1857: 1852: 1847: 1844:(2): 129–46. 1843: 1839: 1835: 1828: 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